Various studies in cell lines have previously demonstrated that sphingosine kinase 1 (SK1) and extracellular signal-regulated kinase 1/2 (ERK-1/2) interact in an estrogen receptor (ER)-dependent manner to influence both breast cancer cell growth and migration. A cohort of 304 ER-positive breast cancer patients was used to investigate the prognostic significance of sphingosine 1-phosphate (S1P) receptors 1, 2, and 3 (ie, S1P 1 , S1P 2 , and S1P 3 ), SK1, and ERK-1/2 expression levels. Expression levels of both SK1 and ERK-1/2 were already available for the cohort, and S1P 1 , S1P 2 , and S1P 3 levels were established by immunohistochemical analysis. High membrane S1P 1 expression was associated with shorter time to recurrence (P ‫؍‬ 0.008). High cytoplasmic S1P 1 and S1P 3 expression levels were also associated with shorter disease-specific survival times (P ‫؍‬ 0.036 and P ‫؍‬ 0.019, respectively). Those patients with tumors that expressed high levels of both cytoplasmic SK1 and ERK-1/2 had significantly shorter recurrence times than those that expressed low levels of cytoplasmic SK1 and cytoplasmic ERK-1/2 (P ‫؍‬ 0.00008), with a difference in recurrence time of 10.5 years. Similarly, high cytoplasmic S1P 1 and cytoplasmic ERK-1/2 expression levels (P ‫؍‬ 0.004) and high cytoplasmic S1P 3 expression and cytoplasmic ERK-1/2 expression levels (P ‫؍‬ 0.004) were associated with shorter recurrence times. These results support a model in which the interaction between SK1, S1P 1 , and/or S1P 3 and ERK-1/2 might drive breast cancer progression, and these findings, therefore, warrant further investigation.

We demonstrate here a new concept termed "oncogene tolerance" whereby human EGF receptor 2 (HER2) increases sphingosine kinase 1 (SK1) expression in estrogen receptor-positive (ER ؉ ) MCF-7 HER2 cells and SK1, in turn, limits HER2 expression in a negative-feedback manner. The HER2-dependent increase in SK1 expression also limits p21-activated protein kinase 1 (p65 PAK1) and extracellular signal regulated kinase 1/2 (ERK-1/2) signaling. Sphingosine 1-phosphate signaling via S1P 3 is also altered in MCF-7 HER2 cells. In this regard, S1P binding to S1P 3 induces a migratory phenotype via an SK1-dependent mechanism in ER ؉ MCF-7 Neo cells, which lack HER2. This involves the S1P stimulated accumulation of phosphorylated ERK-1/2 and actin into membrane ruffles/lamellipodia and migration. In contrast, S1P failed to promote redistribution of phosphorylated ERK-1/2 and actin into membrane ruffles/lamellipodia or migration of MCF-7 HER2 cells. However, a migratory phenotype in these cells could be induced in response to S1P when SK1 expression had been knocked down with a specific siRNA or when recombinant PAK1 was ectopically overexpressed. Thus, the HER2-dependent increase in SK1 expression functions to desensitize the S1P-induced formation of a migratory phenotype. This is correlated with improved prognosis in patients who have a low HER1-3/SK1 expression ratio in their ER ؉ breast cancer tumors compared to patients that have a high HER1-3/SK1 expression ratio."Oncogene addiction" is a term that has been used to describe the reliance of cancer cells on the continued expression of oncogenes in order to maintain the diseased phenotype, progression, and metastasis of the cancer cell (39). Oncogene addiction is intrinsically susceptible to cross talk and feedback regulation that reflects abnormal signaling wiring in the cancer cell and which potentially makes these cells more susceptible to drug intervention at the level of the oncogene than normal cells. HER2 is a well-established oncogene that has an important role in enhancing breast cancer progression (2). The importance of its functional role as an addictive oncogene is exemplified by the fact that targeting HER2 with antibody mediated therapies, such as herceptin, demonstrates significant clinical efficacy (40). Indeed, this approach is in line with the concept that oncogene addiction is the "Achilles heel" of the cancer cell.There are four members of the human epidermal growth factor (EGF) receptor-related family, termed HER1 to HER4. The HER2/neu (c-erbB-2) gene encodes a 185-kDa transmembrane receptor tyrosine kinase, which is similar in amino acid sequence to other members of the EGF receptor family (30). Moreover, the overexpression of HER2/neu and gene amplification is found in up to 30% of primary breast cancers, and its expression is correlated with increased tumor invasion, poor prognosis, and therapeutic resistance (2). Overexpression of HER2 is also associated with downregulation of the estrogen receptor (ER) but not necessarily the complete elimination of...

Sphingosine kinase is an enzyme that catalyses the phosphorylation of sphingosine to form sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane sphingosine 1-phosphate receptors (S1P 1-5 ) and can regulate intracellular target proteins. We have used immunohistochemical analysis to determine the concurrent expression levels of sphingosine kinase 1 or S1P receptors and other signaling proteins in estrogen receptor-positive breast cancer tumors and have then assessed the impact of these combinations on clinical outcome. This approach has enabled identification of (i) novel biomarkers and (ii) several spatially controlled associations between either sphingosine kinase 1 or S1P 1-3 and other signaling proteins whose combination affect prognosis. For instance, the translocation of sphingosine kinase 1 to the plasma membrane has been shown to be a critical determinant in cancer progression. However, our findings identify an additional novel role for the nuclear localization of sphingosine kinase 1 combined with either ERK-1/2 or SFK or LYN or AKT or NF-jB, which significantly shortens disease-specific survival and/or recurrence. We also demonstrate that nuclear S1P 2 receptor and c-SRC are associated with improved prognosis and this is linked with a reduction in the nuclear localization of sphingosine kinase 1. These findings identify potential novel biomarker associations, which might serve as new targets for drug intervention designed to improve treatment of estrogen receptorpositive breast cancer.

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The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo . Here we describe a targeted nanocarrier that delivers in vitro -transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.

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